An unusual electronic effect of an aromatic-F in phase-transfer catalysts derived from cinchona-alkaloid.

Article abstract of DOI:10.1021/ol0267679

[structure: see text] Various N-benzylcinchonidinium salts were prepared to study electronic factors in the catalytic enantioselective phase-transfer alkylation of glycine anion equivalent. An ortho-fluoro substituent on the benzyl group in the quaternary

Full text of DOI:10.1021/ol0267679

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4245-4248
An Unusual Electronic Effect of an
Aromatic-F in Phase-Transfer Catalysts
Derived from Cinchona-Alkaloid
Sang-sup Jew,* Mi-Sook Yoo,† Byeong-Seon Jeong,† Il Yeong Park,‡ and
,†
,†,§
Hyeung-geun Park*
College of Pharmacy, Seoul National UniVersity, Seoul 151-742, Korea, and
College of Pharmacy, Chungbuk National UniVersity, Cheongju 361-763, Korea
ssjew@plaza.snu.ac.kr
Received August 22, 2002
ABSTRACT
Various N-benzylcinchonidinium salts were prepared to study electronic factors in the catalytic enantioselective phase-transfer alkylation of
glycine anion equivalent. An ortho-fluoro substituent on the benzyl group in the quaternary ammonium salt dramatically increased the
enantioselectivity in the alkylation. O(9)-Allyl-N-2′,3′,4′-trifluorobenzylhydrocinchonidinium bromide (27), which gave the highest enantioselectivity
of the catalysts studied, was used to prepare 12 r-alkylated amino acid derivatives in 94∼>99% ee.
Recently, Cinchona alkaloid ammonium salts have been
developed as efficient chiral phase-transfer catalysts.1 Since
the first application of 1 in the alkylation of glycine imine
derivatives by the O’Donnell group,2 more efficient catalysts
2 were independently developed by the Lygo group3 and the
Corey group4 by the introduction of the bulky N-9-anthra-
cenylmethyl group instead of the N-benzyl group in 1. On
the basis of the positive influence of a bulky subunit on the
N(1)-position, the dimeric catalysts 3 were also introduced
as practical phase-transfer catalysts for the synthesis of both
natural and nonnatural R-amino acids (Figure 1).5
* Corresponding authors.
† Seoul National University.
‡ Chungbuk National University.
§ E-mail address (H.-g.P.): hgpk@plaza.snu.ac.kr.
(1) (a) Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc.
1984, 106, 446. (b) Shioiri, T.; Arai, S. In Stimulating Concepts in
Chemistry; Vogtle, F., Stoddart, J. F., Shibasaki, M., Eds.; Wiley-VCH:
Weinheim, Germany, 2000; pp 123-143. (c) O’Donnell, M. J. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York,
2000; Chapter 10. (d) O’Donnell, M. J. Aldrichim. Acta 2001, 34, 3.
(2) (a) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc.
1989, 111, 2353. (b) O’Donnell, M. J.; Wu, S.; Huffman, J. C. Tetrahedron
1994, 50, 4507. (c) O’Donnell, M. J.; Wu, S.; Esikova, I.; Mi, A. U.S.
Patent 5,554,753, 1996. (d) O’Donnell, M. J.; Delgado, F.; Hostettler, C.;
Schwesinger, R. Tetrahedron Lett. 1998, 39, 8775. (e) O’Donnell, M. J.;
Delgado, F.; Pottorf, R. S. Tetrahedron 1999, 55, 6347.
(3) (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595.
(b) Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron Lett. 1999, 40, 1385.
(c) Lygo, B. Tetrahedron Lett. 1999, 40, 1389. (d) Lygo, B.; Crosby, J.;
Peterson, J. A. Tetrahedron Lett. 1999, 40, 8671.
Figure 1. Phase-transfer catalysts derived from Cinchona alkaloid.
10.1021/ol0267679 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/05/2002

substituted at the ortho-, meta-, or para-position with various
functional groups such as methyl, tert-butyl, methoxy, nitro,
halides, and so on. Their catalytic efficiencies were evaluated
by enantioselective phase-transfer alkylation, using 10 mol
% catalyst, N-(diphenylmethylene)glycine tert-butyl ester 4,
benzyl bromide, and 50% aqueous KOH in toluene/
chloroform (volume ratio ) 7:3) at 0 °C for 4-8 h.
We expected that electron-withdrawing functional groups
might increase the enantioselectivity by the formation of a
tighter binding ion pair, which would lead to a more rigid
conformation. However, the meta- and the para-substituted
derivatives did not show any significant difference in
enantioselectivity, despite their electronic properties (data not
shown). In the case of the ortho-substituted derivatives, bulky
groups generally reduced the enantioselectivity. Notably,
among the ortho-substituted derivatives, the 2′-F derivative
7 (89% ee) showed an enhanced enantioselectivity relative
to 6 (74% ee) even though the sizes of F and H are similar
(Table 1). A similar aromatic-F effect was previously
observed by the replacement of the 3,4,5-trifluorobenzene
group with a bulky naphthyl substituent in (S)-binaphthol-
derived C2-symmetric chiral catalysts.7 Also it has been
reported that various aromatic-F groups play an important
role in the binding of enzyme inhibitors.8 These findings
encouraged us to prepare various F-substituted derivatives
(Figure 2).
Table 1. Catalytic Enantioselective Phase-Transfer Alkylationa
temp
(°C)
time
(h)
yieldb
(%)
% eec
(configurationd)
entry
catalyst
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
6
7
8
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
5
6
4
7
6
5
6
7
8
6
5
5
6
5
4
6
7
7
4
7
4
6
4
7
4
6
92
93
90
92
90
93
89
90
91
88
93
91
88
90
85
91
89
93
90
88
90
91
90
93
90
92
74 (S)
89 (S)
74 (S)
75 (S)
92 (S)
90 (S)
59 (S)
76 (S)
71 (S)
50 (S)
92 (S)
66 (S)
62 (S)
72 (S)
50 (S)
68 (S)
22 (S)
54 (S)
92 (S)
94 (S)
95 (S)
97 (S)
92 (S)
95 (S)
96 (S)
98 (S)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
24
25
25
26
26
27
27
0
0
-20
0
-20
0
-20
0
-20
a Reaction was carried out with 5.0 equiv of benzyl bromide and 13.0
equiv of 50% aqueous KOH in the presence of 10 mol % 6-27 in toluene/
chloroform (volume ratio ) 7:3) under the given conditions. b Isolated
yields. c Enantiopurity was determined by HPLC analysis of the benzylated
imine 5f using a chiral column (DAICEL Chiralcel OD) with hexanes/2-
propanol (volume ratio ) 500:2.5) as a solvent. d Absolute configuration
was determined by comparison of the HPLC retention time with that of an
independently prepared authentic sample.2-5
Although several efficient catalysts have been developed
on the basis of steric factors, the electronic factor was not
systematically studied.6 As part of our program for the
mechanistic study of alkylation, we investigated the role of
the electronic factor in Cinchona alkaloid-type phase-transfer
catalysts. Since the ion pair of the quaternary ammonium
cation and the anionic substrate is an important intermediate
for the chiral induction, the electronic effects of the N(1)-
substituents might influence the enantioselectivity. In this
letter, we report the role of electronic factors and the unusual
aromatic-F effect in alkylations of a glycine anion equivalent
involving phase-transfer catalysts.
Figure 2. N-(Fluorobenzyl)cinchonidinium bromide derivatives.
As shown in Table 1, there are, depending on the position
substituted with a fluoro group, quite dramatic variations in
(5) (a) Jew, S.-S.; Jeong, B.-S.; Yoo, M.-S.; Huh, H.; Park, H.-G. Chem.
Commun. 2001, 1244. (b) Park, H.-G.; Jeong, B.-S.; Yoo, M.-S.; Park, M.-
K.; Huh, H.; Jew, S.-S. Tetrahedron Lett. 2001, 42, 4645. (c) Park, H.-G.;
Jeong, B.-S.; Yoo, M.-S.; Lee, J.-H.; Park, M.-K.; Lee, Y.-J.; Kim, M.-J.;
Jew, S.-S. Angew. Chem., Int. Ed. 2002, 41, 3036.
(6) In early studies, the Merk group found that a p-trifluoromethyl group
was important for optimal enantioselectivity; see ref 1a. See also refs 1b-c
for discussions concerning other catalyst studies.
First, the N-benzylcinchonidinium bromide derivatives
were prepared from cinchonidine and benzyl bromides
(7) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc.
2000, 122, 5228.
(8) (a) Kim, C.-Y.; Chandra, P. P.; Jain, A.; Christionson, D. W. J. Am.
Chem. Soc. 2001, 123, 9620. (b) Doyon, J. B.; Jain, A. Org. Lett. 1999, 1,
183. (c) Madder, R. D.; Kim, C.-Y.; Chandra, P. P.; Doyon, J. B.; Baird,
T. A., Jr.; Fierke, C. A.; Christionson, D. W.; Voet, J. G.; Jain, A. J. Org.
Chem. 2002, 67, 582.
(4) (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119,
12414. (b) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39,
5347. (c) Corey, E. J.; Bo, Y.; Busch-Peterson, J. J. Am. Chem. Soc. 1998,
120, 13000.
4246
Org. Lett., Vol. 4, No. 24, 2002

Figure 3. Stereoscopic view of 7 drawn by ORTEPII. Selected atomic distances (Å) and bond angles and torsion angles (deg): N1ΛBr
4.119(2), F(a)ΛO1 4.100(3), F(b)ΛBr 3.492(6); C2-N1-C12 109.8(2), N1-C12-C1′ 113.9(2); C2-N1-C12-C1′-59.6(2), C8-N1-
C12-C1′-175.2(2). Non-carbon atoms are drawn as hatched ellipsoids, and hydrogen atoms are drawn as small circles of arbitrary radii.
the enantioselectivity. Generally, a single fluoro group in
the ortho-position is critical for enhancement of the induction.
With the exception of o,o′-difluoro groups, which are not
effective, the number of fluoro groups on the aromatic ring
is not directly related to the enantioselectivity. The best
results were obtained with additional fluoro groups on the
3′- and/or 4′-positions (10, 92% ee; 11, 90% ee; 16, 92%
ee).
the reaction was conducted at -20 °C. Very high enantio-
selectivities (94∼>99% ee) are shown in Table 2, indicating
that catalyst 27 is a very efficient asymmetric phase-transfer
Table 2. Catalytic Enantioselective Phase-Transfer Alkylationa
To study the role of 2′-F in the enantioselectivity, an X-ray
crystal structure of 7 was obtained (Figure 3).9 The confor-
mation of 7 is similar to that of the unsubstituted parent 6.2b
However, the 2′-F of 7 is disordered; the phenyl group
occupies two different conformations in unequal amounts:
four parts as F(a) and one part as F(b). This might be due to
unfavorable anionic repulsion between the bromide anion
and F(b). Another possibility is that conformation F(a) could
be favored due to internal hydrogen bonding involving water
between F(a) and the C(9)OH group (the distance between
these groups in the crystal structure is 4.1 Å). While the exact
mechanistic details of the induction are not clear at this time,
2′-F might be involved in internal hydrogen bonding involv-
ing water in order to maintain a more rigid catalyst
conformation.10,11
Another possible reason might be associated with the
induced dipole moment by the unsymmetrical introduction
of a fluoro group on the benzene ring, which could allow
formation of a more favorable ion pair intermediate with the
anionic enolate substrate.6a The precise mechanistic role of
2′-F is now under investigation.
Dihydro and C(9)O-allyl derivatives of 7, 10, 11, and 16
were prepared by the reported method,5 and their catalytic
efficiencies were evaluated (24-27). In agreement with
previous reports,2b,c,3a all of these catalysts gave higher
enantioselectivities than those with a free C(9)OH group
(92-96% ee at 0 °C). Use of lower temperature improved
the enantioselectivity (94-98% ee at -20 °C).
The best enantioselectivity was obtained with catalyst 27,
which was chosen for further investigation with various alkyl
halides. Table 2 shows the results obtained for the alkylation
of 4 with various alkyl halides, using catalyst 27 under the
same reaction conditions as those in Table 1, except that
a With the exception of the alkyl halide used and the reaction temperature,
the reaction conditions and determination of the enantiopurity and absolute
configuration were same as that in Table 1.
Org. Lett., Vol. 4, No. 24, 2002
4247

catalyst for the synthesis of natural and nonnatural R-amino
acids.
Among the F-substituted derivatives, O(9)-allyl-N-2′,3′,4′-
trifluorobenzylhydrocinchonidinium bromide, 27, showed
the highest enantioselectivity. The easy and efficient prepara-
tion of 27 makes it an attractive catalyst for the preparation
of various R-amino acid derivatives in high enantioselectivity.
In conclusion, various N-(substituted-benzyl)cinchonidin-
ium salts were prepared for study of the electronic factors
in the catalytic enantioselective phase-transfer alkylation of
glycine anion equivalent 4. Unexpectedly, a 2′-F substituent
dramatically increased the enantioselectivity in the alkylation.
Acknowledgment. This work was supported by grants
from Aminogen Co., Korea, via the Research Center of New
Drug Development of Seoul National University, the Re-
search Institute of Pharmaceutical Sciences in the College
of Pharmacy of Seoul National University, and the Korea
Health 21 R&D Project, Ministry of Health & Welfare,
Republic of Korea (01-PJ2-PG6-01NA01-0002).
(9) Crystallographic data of 7: C26H28BrFN2O‚1.5 H2O, bright yellow
prism, 0.30 × 0.30 × 0.30 mm, tetragonal, space group P41212 (no. 92), a
) b ) 10.029(1) Å, c ) 47.637(7) Å, V ) 4791(1) Å3, Z ) 8, Fcalcd
)
1.415 g/cm3, µ(Cu KR) ) 26.6 cm-1, T ) 298 K. Details of structural
results were deposited to the Cambridge Crystallographic Data Center as
deposit no. 190336. These data can be obtained free of charge via the
Internet at http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax, +44 1223 336033;
e-mail, deposit@ccdc.cam.ac.uk).
Supporting Information Available: Representative ex-
perimental procedures and an X-ray crystal structure of 7
and spectroscopic characterizations of catalyst 27 and alky-
lated imines 5i and 5l. This material is available free of
charge via the Internet at http://pubs.acs.org.
(10) Alkylations under anhydrous conditions using 10 mol % catalyst,
the O(9)-allyl derivative of 6 or 7 along with N-(diphenylmethylene)glycine
tert-butyl ester 4, benzyl bromide, and NaH in toluene/CH2Cl2 (volume
ratio ) 7:3) at 0 °C for 12 h both gave the same enantioselectivity (62%
ee).
(11) Thalladi, V. R.; Weiss, H.-C.; Blaeser, D.; Boese, R.; Nangia, A.;
Desiraju, G. R. J. Am. Chem. Soc. 1998, 120, 8702.
OL0267679
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